Alisol B regulates AMPK/mTOR/SREBPs via directly targeting VDAC1 to alleviate hyperlipidemia.

BACKGROUND: The occurrence of hyperlipidemia is significantly influenced by lipid synthesis, which is regulated by sterol regulatory element binding proteins (SREBPs), thus the development of drugs that inhibit lipid synthesis has become a popular treatment strategy for hyperlipidemia. Alisol B (ALB), a triterpenoid compound extracted from Alisma, has been reported to ameliorate no-nalcoholic steatohepatitis (NASH) and slow obesity. However, the effect of ALB on hyperlipidemia and mechanism are unclear. PURPOSE: To examine the therapeutic impact of ALB on hyperlipidemia whether it inhibits SREBPs to reduce lipid synthesis. STUDY DESIGN: HepG2, HL7702 cells, and C57BL/6J mice were used to explore the effect of ALB on hyperlipidemia and the molecular mechanism in vivo and in vitro. METHODS: Hyperlipidemia models were established using western diet (WD)-fed mice in vivo and oleic acid (OA)-induced hepatocytes in vitro. Western blot, real-time PCR and other biological methods verified that ALB regulated AMPK/mTOR/SREBPs to inhibit lipid synthesis. Cellular thermal shift assay (CETSA), molecular dynamics (MD), and ultrafiltration-LC/MS analysis were used to evaluate the binding of ALB to voltage-dependent anion channel protein-1 (VDAC1). RESULTS: ALB decreased TC, TG, LDL-c, and increased HDL-c in blood, thereby ameliorating liver damage. Gene set enrichment analysis (GSEA) indicated that ALB inhibited the biosynthesis of cholesterol and fatty acids. Consistently, ALB inhibited the protein expression of n-SREBPs and downstream genes. Mechanistically, the impact of ALB on SREBPs was dependent on the regulation of AMPK/mTOR, thereby impeding the transportation of SREBPs from endoplasmic reticulum (ER) to golgi apparatus (GA). Further investigations indicated that the activation of AMPK by ALB was independent on classical upstream CAMKK2 and LKB1. Instead, ALB resulted in a decrease in ATP levels and an increase in the ratios of ADP/ATP and AMP/ATP. CETSA, MD, and ultrafiltration-LC/MS analysis indicated that ALB interacted with VDAC1. Molecular docking revealed that ALB directly bound to VDAC1 by forming hydrogen bonds at the amino acid sites S196 and H184 in the ATP-binding region. Importantly, the thermal stabilization of ALB on VDAC1 was compromised when VDAC1 was mutated at S196 and H184, suggesting that these amino acids played a crucial role in the interaction. CONCLUSION: Our findings reveal that VDAC1 serves as the target of ALB, leading to the inhibition of lipid synthesis, presents potential target and candidate drugs for hyperlipidemia.

Tensorizing GAN With High-Order Pooling for Alzheimer's Disease Assessment.

It is of great significance to apply deep learning for the early diagnosis of Alzheimer's disease (AD). In this work, a novel tensorizing GAN with high-order pooling is proposed to assess mild cognitive impairment (MCI) and AD. By tensorizing a three-player cooperative game-based framework, the proposed model can benefit from the structural information of the brain. By incorporating the high-order pooling scheme into the classifier, the proposed model can make full use of the second-order statistics of holistic magnetic resonance imaging (MRI). To the best of our knowledge, the proposed Tensor-train, High-order pooling and Semisupervised learning-based GAN (THS-GAN) is the first work to deal with classification on MR images for AD diagnosis. Extensive experimental results on Alzheimer's disease neuroimaging initiative (ADNI) data set are reported to demonstrate that the proposed THS-GAN achieves superior performance compared with existing methods, and to show that both tensor-train and high-order pooling can enhance classification performance. The visualization of generated samples also shows that the proposed model can generate plausible samples for semisupervised learning purpose.

Protection of hepatocyte mitochondrial function by blueberry juice and probiotics via SIRT1 regulation in non-alcoholic fatty liver disease.

Mitochondrial dysfunction has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Our previous study has firstly reported that blueberry juice and probiotics (BP) effectively protect liver function in NAFLD. However, the role of BP in hepatic mitochondria is unknown. Here, we aimed to investigate the effects and mechanisms of BP on the mitochondrial function and oxidative stress of rats with NAFLD. The NAFLD rat models were established and treated with BP and SIRT1 siRNA. The mitochondrial ultrastructure was analyzed by electron microscopy, reactive oxygen species (ROS) was detected by immunofluorescence, and biomarkers of mitochondrial function and oxidative stress were examined via quantitative reverse transcription-PCR, western blot, and immunohistochemistry. Results revealed that BP significantly reversed the NAFLD-induced hepatic mitochondrial damage, mitochondrial swelling, and hepatic necrosis. In particular, BP significantly restored the mitochondrial respiratory function of NAFLD rats by decreasing state 4 and 3 respiration rates, by increasing the respiration control ratio (RCR) and the ADP/O ratio, and by enhancing ATP, ADP, AMP, and EC syntheses. Moreover, BP reduced mitochondrial oxidative stress in NAFLD by decreasing the MDA level, elevating the GSH and SOD levels, and suppressing the ROS activity. Importantly, SIRT1 deficiency significantly abolished the effects of BP on the mitochondria and oxidative stress. Furthermore, BP reversed the decline of PGC-1α expression induced by NAFLD, while SIRT1 silencing significantly suppressed the effects of BP on PGC-1α. In conclusion, BP might effectively protect rats against mitochondrial dysfunction during NAFLD as potential ingredients of functional food, by modulating the SIRT1 expression. Potential endogenous modulators of NAFLD pathogenesis may ultimately provide novel tools for therapeutic intervention.

Application of response surface methodology to optimise extraction of flavonoids from fructus sophorae.

Response surface methodology (RSM) based on a central composite design (CCD) was applied to optimise the extraction conditions for flavonoids from fructus sophorae with advantages in terms of resisting flavonoids during the whole process and maximising of extraction yield. Three aglycon forms of the flavonoids, namely, quercetin, kaempferol and isorhamnetin were quantified by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) to estimate extraction yield. The combined effects of independent variables were studied and the optimal extraction conditions were obtained as ethanol concentration, 74.47%; solid-liquid ratio, 17.99 ml/g; temperature, 89.13°C; and extraction time, 2.10h. The reliability of the method was confirmed by recovery experiments, performed under optimal conditions. Recoveries indicated that flavonoids resisted the extraction conditions. The experimental extraction yield under optimal conditions was found to be 10.459%, which was well matched with the predicted values of 10.461%.

Analysis of phthalate migration from plastic containers to packaged cooking oil and mineral water.

The migration of phthalates (PAEs), a class of typical environmental estrogen contaminants in food, from food packaging to packaged food attracts more and more attention worldwide. Many factors will affect the migration processes. The purpose of this study was to evaluate PAE migration from plastic containers to cooking oil and mineral water packed in authentic commercial packaging and stored under various conditions (different storage temperatures, contact times, and storage states (static or dynamic state)) and to identify a potential relationship between the amount and type of PAEs migrated and the lipophilic character of the food matrix. The samples were analyzed by a novel method of liquid chromatography combined with solid-phase extraction by an electrospun nylon 6 nanofibers mat, with PAE detection limits of 0.001 µg/L in mineral water and 0.020 µg/L in cooking oil, respectively. The results demonstrated that the cooking oil was a more suitable medium for the migration of PAEs from packages into foodstuffs than mineral water. Scilicet, the migration potential of the PAEs into foodstuffs, depends on the lipophilic characteristics of the food matrix. The results also demonstrated that migrations were more significant at higher temperature, longer contact time, and higher dynamic frequency; thus, the migration tests should be evaluated with consideration of different storage temperatures and contact times. Mathematical models with good logarithmic relationships were established to demonstrate the relationship between the PAE migration and food/packaging contact time for different storage temperatures. These established mathematical models would be expected to become a set of practical tools for the prediction of PAE migration.